When administered orally or via another non-parenteral route many bioactive ingredients suffer from a poor pharmacokinetic profile due to fast elimination and metabolisation. Parenteral administration methods therefore are often the only option available. However multiple daily injections are often required in order to maintain steady-state supply of bioactive ingredients. This not only is cumbersome but also negatively impacts patient compliance. A solution to increase patient compliance is by reducing the number of injections to one per day, week or month by the use of controlled-drug delivery vehicles.
One option to achieve this goal is the incorporation of the bioactive ingredients into a hydrogel. Hydrogels are defined as three-dimensional physical or covalently cross-linked networks that are able to absorb a large amount of water while maintaining a semisolid morphology. The networks in hydrogels are able to retain up to 99.99% water making them very interesting candidates for carrying active ingredients and biomaterials. The hydrogel network can encapsulate and release therapeutics via various mechanisms, such as (de)swelling, external triggers: pH or temperature, erosion or diffusion. Hydrogel matrices moreover possess the capability to encapsulate and release therapeutics in a sustained manner over prolonged periods of time.
For biomedical applications, like tissue engineering, medical imaging or controlled drug delivery, the predominant class under investigation still remains the family of chemical hydrogels in which the polymeric network is held together by cross-links formed by chemical bonds. However, for in vivo applications these polymeric cross-linked structures often lack important requirements like stability in biological fluids, low toxicity and poor immunogenicity, especially when crosslinking is done in vivo.
Hydrogels prepared from cross-linked synthetic polymers possess various disadvantages such as (i) monomer and degradation product toxicity (e.g. toxic cross-linkers, like gluteraldehyde or local acidification due to degradation products of PLGA and analogues), (ii) in vivo uncontrollable polymer swelling can cause pain in the host, (iii) non-uniform polymers possess different pore sizes and concomitant different release properties, and (iv) unwanted burst effects and release of active ingredient over brief periods of time due to large pores in the polymer network. In addition most synthetic (chemically cross-linked) polymers can only be administered via minor surgery. Biopolymers such as collagen, gelatin and fibrin on the other hand do not possess clinical human applications due to their origin and the risk of inflammatory host response from viruses or bacteria.
To cope with the problems associated with hydrogels based on synthetic polymers, self-assembling peptide hydrogels have been developed as suitable alternatives to synthetic polymer hydrogels. Peptide based hydrogels are formed by molecular self-assembly of the native peptides to nanoscale fibers. Self-assembling peptide hydrogels offer interesting properties, such as shear-thinning, lack of in vivo toxicity and immunogenicity, good biocompatibility and biodegradability, making them fit for in vivo use with applications in the field of drug delivery and tissue engineering. The peptides can be readily prepared using standard peptide synthesis methods and by selection of the amino acid building blocks the amino acid sequence can be conveniently customized to tunable mechanical and release properties.
Various α-peptide sequences have been described as having hydrogel-forming properties under physiological conditions. Most of these possess an amphipatic structure wherein the peptide sequence either consists of alternating polar and apolar amino acids or contains a large hydrophobic end-group such as Fmoc.
Challenges in developing hydrogel-forming peptides are the selection of appropriate amino acids from the great diversity of available residues, their proneness to degradation by proteolytic enzymes, as well as the need to provide biocompatible, biodegradable and functional soft materials. A balance between hydrophobicity and hydrophilicity needs to be maintained when designing oligopeptide hydrogels in order to obtain a self-assembled system under suitable conditions. However, upon use of oligopeptide hydrogels as injectable controlled-delivery systems, challenges with regard to drug release rate, mechanism of release, determination of toxicity, fine-tuning of viscoelastic and release properties and assessing its biological stability still need to be addressed.
An important criterion for drug delivery from peptide hydrogels consists in an acceptable enzymatic stability to maintain sufficient control over the release of active components from a hydrogel matrix. In this context α-peptide hydrogelators that are easily cleaved by endo- and exopeptidases, could possess insufficient enzymatic stability leading to in vivo burst effects and destabilization of the supramolecular system. In addition, the previously mentioned amphipatic α-oligopeptides are reported to exhibit hours-to-days release profiles of various encapsulated compounds. However, these drug-delivery systems do not entirely meet the need for patients suffering from chronical diseases such as ALS, Alzheimer's disease, diabetes, and heart diseases. Indeed, longer term sustained delivery of pharmaceuticals is desirable, preferably during periods exceeding 24 hours such as several days or weeks. This not only would increase patient's comfort by decreasing the amount of injections required for efficient treatment, but also be beneficial in terms of compliance.
A growing area of interest for peptide hydrogels is that of tissue engineering, which involves the use of living cells as building blocks to repair or replace portions of or whole tissues, e.g. bone, cartilage, blood vessels, bladder, skin, muscle, etc. Cells are typically implanted or ‘seeded’ into an artificial structure capable of supporting three-dimensional tissue formation. These structures, called scaffolds, serve as support while mimicking the in vivo environment of the cells. Scaffolds can be made of different materials, which can be of natural or synthetic sources and can be biodegradable or not. Examples of natural materials include collagen and fibrin, and polysaccharidic materials, like chitosan or glycosaminoglycans (GAGs), while synthetic materials include biodegradable polyesters such as PLGA and its analogues. Hydrogel based scaffolds have been developed of which peptide based hydrogels have gained particular interest because of the properties mentioned above and in particular their good cell compatibility.
Although the current peptide based hydrogels offer attractive properties there still is room for improvement in particular as regards their mechanical and biological properties such as biocompatibility, improved immunogenicity and toxicity profile, as well as drug delivery characteristics.
Journal of Materials Chemistry B, 2015, 3, 759-765 describes an α-amino acid hexapeptide hydrogelator for controlled-release drug delivery. Angew. Chem. Int. Ed. 2013, 32, 8266-8270 reports 14-helical N-Acetyl-capped 3-peptides, which lead to supramolecular self-assembly resulting in nano- to macroscale fiber formation. Int. J. of Biological Macro. 2005, 36, 232-240 describes peptides with alternating hydrophobic and polar amino acids that form stable 3-sheet secondary structures and self-assemble into hydrogel-like matrices in the presence of physiological salt concentrations.
WO 2013/072686 describes self-assembling peptides α-amino acids that coalesce such that they self-assemble to form a hydrogel. US 2005/0181973 discloses self-assembling peptides of two-amino acid domains for use as scaffolds in cell culture, tissue engineering and tissue repair. US2014/0302144 discloses pharmaceutical formulations comprising self-assembling peptides for sustained delivery of therapeutic agents.